{"entity": "researcher", "timestamp": "2026-07-17T09:07:46.394Z", "family": "Heldin", "given": "Carl-Henrik", "initials": "CH", "orcid": "0000-0002-9508-896X", "affiliations": ["Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Box 582, Uppsala University, SE-751 23, Uppsala, Sweden. c-h.heldin@imbim.uu.se."], "links": {"self": {"href": "https://publications.scilifelab.se/researcher/f705f7c509904a1db721ace2267ca48f.json"}, "display": {"href": "https://publications.scilifelab.se/researcher/f705f7c509904a1db721ace2267ca48f"}}, "publications": [{"entity": "publication", "iuid": "d831391ebc12404d9d3e99a061f12e86", "links": {"self": {"href": "https://publications.scilifelab.se/publication/d831391ebc12404d9d3e99a061f12e86.json"}, "display": {"href": "https://publications.scilifelab.se/publication/d831391ebc12404d9d3e99a061f12e86"}}, "title": "Targeting oncogenic T\u03b2RI signaling inhibits androgen-independent prostate cancer growth and metastasis.", "authors": [{"family": "Flodbring Larsson", "given": "Per", "initials": "P"}, {"family": "Schmidt", "given": "Alexej", "initials": "A", "orcid": "0000-0002-1185-3012", "researcher": {"href": "https://publications.scilifelab.se/researcher/3708b225fbae4c239bdc3bea34beff17.json"}}, {"family": "Mu", "given": "Yabing", "initials": "Y", "orcid": "0000-0003-3193-1425", "researcher": {"href": "https://publications.scilifelab.se/researcher/626d44f4c6d7498ea7e2690e9f7008d5.json"}}, {"family": "Zang", "given": "Guangxiang", "initials": "G"}, {"family": "Song", "given": "Jie", "initials": "J", "orcid": "0000-0002-4955-9118", "researcher": {"href": "https://publications.scilifelab.se/researcher/cfb760d62cfc4eda9e18a6d618345334.json"}}, {"family": "Gajavilli", "given": "Vishnupriya", "initials": "V"}, {"family": "Tao", "given": "Junting", "initials": "J"}, {"family": "Rakhimova", "given": "Olena", "initials": "O", "orcid": "0000-0002-3536-4467", "researcher": {"href": "https://publications.scilifelab.se/researcher/727f418f4ea24859ba4bf0e4bdf1f64c.json"}}, {"family": "Ericsson", "given": "Madelene", "initials": "M"}, {"family": "Aripaka", "given": "Karthik", "initials": "K", "orcid": "0000-0001-5071-6187", "researcher": {"href": "https://publications.scilifelab.se/researcher/2622fdbe964f4f99810cdc20c67a9fe0.json"}}, {"family": "Halin Bergstr\u00f6m", "given": "Sofia", "initials": "S"}, {"family": "Yuan", "given": "Wei", "initials": "W"}, {"family": "Bogdan", "given": "Denisa", "initials": "D"}, {"family": "Zhang", "given": "Aaron Huairen", "initials": "AH"}, {"family": "Welti", "given": "Jon", "initials": "J"}, {"family": "Bergh", "given": "Anders", "initials": "A", "orcid": "0000-0001-5163-5821", "researcher": {"href": "https://publications.scilifelab.se/researcher/ba7945f3e27f4628ba29c7003b3bdf36.json"}}, {"family": "de Bono", "given": "Johann", "initials": "J"}, {"family": "Heldin", "given": "Carl-Henrik", "initials": "CH", "orcid": "0000-0002-9508-896X", "researcher": {"href": "https://publications.scilifelab.se/researcher/f705f7c509904a1db721ace2267ca48f.json"}}, {"family": "Landstr\u00f6m", "given": "Mar\u00e9ne", "initials": "M", "orcid": "0000-0001-6737-7230", "researcher": {"href": "https://publications.scilifelab.se/researcher/c2f02fcfb1c1497d81a6f343bc0e6928.json"}}], "type": "journal article", "published": "2026-06-17", "journal": {"title": "Signal Transduct Target Ther", "issn": "2059-3635", "volume": "11", "issue": "1", "issn-l": null}, "abstract": "Metastatic castration-resistant prostate cancer (mCRPC) remains the primary cause of prostate cancer-related mortality. Despite the availability of treatments, the molecular mechanisms underlying tumor invasion and metastasis are not fully understood, highlighting the need for novel therapeutic strategies. In this study, we developed fully human monoclonal antibodies (mAbs) that prevent the proteolytic cleavage of the transforming growth factor-beta (TGF\u03b2) type I receptor (T\u03b2RI) by steric hindrance. This cleavage, mediated by the metalloprotease ADAM17 (a disintegrin and metalloprotease domain 17; also known as TACE), results in the generation of a soluble intracellular domain (T\u03b2RI-ICD) that is translocated to the nucleus of castration-resistant prostate cancer (CRPC) cells and promotes epithelial-to-mesenchymal transition (EMT), invasion, and metastasis. High levels of TGFBR1 correlated with poor survival in two independent clinical cohorts of patients with mCRPC, and a strong positive correlation between TGFBR1 and ADAM17 expression was observed. In a preclinical human orthotopic mCRPC mouse model, treatment with therapeutic mAbs effectively prevented the nuclear accumulation of T\u03b2RI-ICD, inhibited EMT, and suppressed tumor growth, invasion, and metastasis. Notably, the therapeutic effect was comparable to that of docetaxel, a current standard-of-care chemotherapy, without noticeable side effects on body weight, proximal aorta or heart function detected in immune-deficient mice. These findings suggest that targeting T\u03b2RI cleavage using specific mAbs is a novel precision medicine approach for the treatment of mCRPC. By selectively blocking the prometastatic activity of T\u03b2RI-ICD without disrupting physiological TGF\u03b2 signaling, this strategy may provide a safer and more effective alternative to existing therapies for advanced prostate cancer.", "doi": "10.1038/s41392-026-02737-x", "pmid": "42303991", "labels": {"Drug Discovery and Development": "Service"}, "xrefs": [{"db": "pii", "key": "10.1038/s41392-026-02737-x"}, {"db": "pmc", "key": "PMC13272619"}], "notes": [], "created": "2026-06-29T07:17:03.522Z", "modified": "2026-07-06T20:10:17.411Z"}, {"entity": "publication", "iuid": "1f47f9fb4e1e4013a73952ad427c61e2", "links": {"self": {"href": "https://publications.scilifelab.se/publication/1f47f9fb4e1e4013a73952ad427c61e2.json"}, "display": {"href": "https://publications.scilifelab.se/publication/1f47f9fb4e1e4013a73952ad427c61e2"}}, "title": "TGF\u03b2 signaling promotes cell cycle progression and resistance to the CDK4/6 inhibitor palbociclib through SOX4 transcriptional modulation in breast cancer cells.", "authors": [{"family": "Ali", "given": "Mohamad Moustafa", "initials": "MM", "orcid": "0000-0002-4902-0550", "researcher": {"href": "https://publications.scilifelab.se/researcher/780c944670ff4d7489410895569ac257.json"}}, {"family": "Itoh", "given": "Yuka", "initials": "Y"}, {"family": "Badji", "given": "Aisha Mariama Pereira", "initials": "AMP"}, {"family": "Gallant", "given": "Sarah", "initials": "S", "orcid": "0009-0003-9742-4706", "researcher": {"href": "https://publications.scilifelab.se/researcher/666f2f479a3e4421b0aa834d49c0d724.json"}}, {"family": "Tsirigoti", "given": "Chrysoula", "initials": "C", "orcid": "0000-0001-6554-738X", "researcher": {"href": "https://publications.scilifelab.se/researcher/369717d5e92a4045b701964c37fd0aa8.json"}}, {"family": "Bai", "given": "Yu", "initials": "Y", "orcid": "0009-0002-0812-8917", "researcher": {"href": "https://publications.scilifelab.se/researcher/a1f57827cead428f8a7d7e4386eca3a3.json"}}, {"family": "Filipek-G\u00f3rniok", "given": "Beata", "initials": "B"}, {"family": "Miyazawa", "given": "Keiji", "initials": "K", "orcid": "0000-0002-7835-7718", "researcher": {"href": "https://publications.scilifelab.se/researcher/71984836d37c463eaf5ded53bed887dc.json"}}, {"family": "Heldin", "given": "Carl-Henrik", "initials": "CH", "orcid": "0000-0002-9508-896X", "researcher": {"href": "https://publications.scilifelab.se/researcher/f705f7c509904a1db721ace2267ca48f.json"}}, {"family": "Moustakas", "given": "Aristidis", "initials": "A", "orcid": "0000-0001-9131-3827", "researcher": {"href": "https://publications.scilifelab.se/researcher/6c1626d991f3485e81232db174537e6d.json"}}], "type": "journal article", "published": "2026-02-04", "journal": {"title": "Cell Death Dis", "issn": "2041-4889", "volume": "17", "issue": "1", "pages": "209", "issn-l": "2041-4889"}, "abstract": "Cancer signaling encompasses a wide array of entangled molecular cascades that promote oncogenic progression and counteract the effect of tumor suppressors. Transforming growth factor \u03b2 (TGF\u03b2) induces complex and stage-dependent effects throughout tumor progression. During pre-malignant hyperplastic growth, TGF\u03b2 restricts cell proliferation and inflammation, while on the other hand, TGF\u03b2 promotes migration and distal metastasis of cancer cells. To dissect the temporal chromatin-based transcriptional response to TGF\u03b2, we employed 3D culture models of isogenic human breast epithelial cells, exemplified by non-oncogenic MCF-10A (MI) and their HRAS-transformed counterpart (MII). Genome-wide chromatin accessibility profiling revealed an extensive chromatin opening induced by TGF\u03b2 at transcription start sites and enhancer elements in both models, with a marked enrichment of SOX4 binding motifs in oncogenic cells. Transcriptomic analyses unexpectedly revealed the upregulation of DNA replication and DNA damage response pathways, following TGF\u03b2 stimulation of oncogenic MII 3D cultures. Canonical TGF\u03b2-driven programs, including epithelial-mesenchymal transition and metabolic reprogramming, were activated in both models. Notably, single-cell RNA-seq of primary breast tumors confirmed co-expression of SOX4 and cell cycle regulators. Mechanistically, we show that TGF\u03b2 induces the interaction between the MH2 domain of SMAD3 and the intrinsically disordered regions of SOX4, co-activating downstream gene targets. Validating the genome-wide analyses, we found that resistance of breast cancer cells to the CDK4/6 inhibitor palbociclib conferred by TGF\u03b2 stimulation was functionally dependent on SOX4. Collectively, our findings reveal an apparent oncogenic function of TGF\u03b2 in promoting cell cycle progression and drug resistance through SOX4, highlighting the pro-tumorigenic role of TGF\u03b2 signaling in breast cancer progression.", "doi": "10.1038/s41419-026-08435-4", "pmid": "41639049", "labels": {"NGI Uppsala (SNP&SEQ Technology Platform)": "Service", "NGI Short read": "Service", "National Genomics Infrastructure": "Service"}, "xrefs": [{"db": "pmc", "key": "PMC12895049"}, {"db": "pii", "key": "10.1038/s41419-026-08435-4"}], "notes": [], "created": "2026-06-01T08:42:55.172Z", "modified": "2026-06-01T08:42:55.598Z"}, {"entity": "publication", "iuid": "e851d932ff224ce9a80844e9e4e5cd2c", "links": {"self": {"href": "https://publications.scilifelab.se/publication/e851d932ff224ce9a80844e9e4e5cd2c.json"}, "display": {"href": "https://publications.scilifelab.se/publication/e851d932ff224ce9a80844e9e4e5cd2c"}}, "title": "The transcription factor LHX2 mediates and enhances oncogenic BMP signaling in medulloblastoma.", "authors": [{"family": "Ohata", "given": "Yae", "initials": "Y"}, {"family": "Ali", "given": "Mohamad M", "initials": "MM", "orcid": "0000-0002-4902-0550", "researcher": {"href": "https://publications.scilifelab.se/researcher/780c944670ff4d7489410895569ac257.json"}}, {"family": "Tsubakihara", "given": "Yutaro", "initials": "Y"}, {"family": "Itoh", "given": "Yuka", "initials": "Y"}, {"family": "Ros\u00e9n", "given": "Gabriela", "initials": "G"}, {"family": "Bergstr\u00f6m", "given": "Tobias", "initials": "T"}, {"family": "Mor\u00e9n", "given": "Anita", "initials": "A"}, {"family": "Gol\u00e1n-Cancela", "given": "Irene", "initials": "I"}, {"family": "Nakada", "given": "Ayana", "initials": "A"}, {"family": "Voytyuk", "given": "Oleksandr", "initials": "O"}, {"family": "Tsuchiya", "given": "Maiko", "initials": "M"}, {"family": "Fukui", "given": "Rei", "initials": "R"}, {"family": "Yamamoto", "given": "Kouhei", "initials": "K"}, {"family": "Mart\u00edn-Rubio", "given": "Paula", "initials": "P", "orcid": "0000-0002-2702-9212", "researcher": {"href": "https://publications.scilifelab.se/researcher/b71065b5619e414bb6401638b76b2160.json"}}, {"family": "Sancho", "given": "Patricia", "initials": "P"}, {"family": "Strell", "given": "Carina", "initials": "C"}, {"family": "Micke", "given": "Patrick", "initials": "P"}, {"family": "Wechsler-Reya", "given": "Robert J", "initials": "RJ"}, {"family": "Hashizume", "given": "Yoshinobu", "initials": "Y"}, {"family": "Miyazono", "given": "Kohei", "initials": "K", "orcid": "0000-0001-7341-0172", "researcher": {"href": "https://publications.scilifelab.se/researcher/7a14a58f628d435a94ad9540478117cb.json"}}, {"family": "Caja", "given": "Laia", "initials": "L", "orcid": "0000-0002-8786-8763", "researcher": {"href": "https://publications.scilifelab.se/researcher/62d8ae2bdac54a6584afeac2b766f628.json"}}, {"family": "Heldin", "given": "Carl-Henrik", "initials": "CH", "orcid": "0000-0002-9508-896X", "researcher": {"href": "https://publications.scilifelab.se/researcher/f705f7c509904a1db721ace2267ca48f.json"}}, {"family": "Swartling", "given": "Fredrik J", "initials": "FJ", "orcid": "0000-0002-8460-4367", "researcher": {"href": "https://publications.scilifelab.se/researcher/69679cebbc90496f9c5b32f56d966654.json"}}, {"family": "Moustakas", "given": "Aristidis", "initials": "A", "orcid": "0000-0001-9131-3827", "researcher": {"href": "https://publications.scilifelab.se/researcher/6c1626d991f3485e81232db174537e6d.json"}}], "type": "journal article", "published": "2025-10-00", "journal": {"title": "Cell Death Differ.", "issn": "1476-5403", "volume": "32", "issue": "10", "pages": "1915-1929", "issn-l": "1350-9047"}, "abstract": "Oncogenic events perturb cerebellar development leading to medulloblastoma, a common childhood brain malignancy. Molecular analyses classify medulloblastoma into the WNT, SHH, Group 3 and Group 4 subgroups. Bone morphogenetic protein (BMP) pathways control cerebellar development and have been linked to the progression of medulloblastoma disease, with major remaining gaps in their mechanistic and clinically-relevant roles. We therefore aimed at exploring BMP mechanisms of action in medulloblastoma. Patient-derived tumors from different subgroups were analyzed in mouse xenografts, complemented by independent tumor immunohistochemical analysis. Cell-based assays analyzed signaling mechanisms. Medulloblastoma cell orthotopic xenografts analyzed tumor growth and metastasis in vivo. Active BMP signaling, detected as nuclear and phosphorylated SMAD1/5, characterized several medulloblastoma subgroups, with enrichment in Group 4, SHH and Group 3 tumors. Spatial transcriptomics in tumor areas, complemented by transcriptomic analysis of multiple cell models, identified BMP-dependent transcriptional induction of the LIM-homeobox gene 2 (LHX2). BMP signaling via SMADs induced LHX2 expression and LHX2 transcriptionally induced BMP type I receptor (ACVR1) expression by association with the proximal promoter region of the ACVR1 gene. BMP signaling and LHX2 gain-of-function expression led to enriched stemness and associated chemoresistance in medulloblastoma cultures. In-mouse orthotopic transplantation of paired primary/recurrent Group 4 medulloblastoma cell populations, correspondingly expressing LHX2-low/BMP-low signaling and LHX2-high/BMP-high signaling, ascribed to the latter (high) group more efficient tumor propagation and spinal cord metastatic potential. Depletion of LHX2 in these recurrent tumor cells suppressed both BMP signaling and tumor propagation in vivo. Thus, LHX2 cooperates with, and enhances, oncogenic BMP signaling in medulloblastoma tumors. The molecular pathway that couples LHX2 function to BMP signaling in medulloblastoma deepens our understanding this malignancy.", "doi": "10.1038/s41418-025-01488-6", "pmid": "40148468", "labels": {"NGI Short read": "Service", "NGI Uppsala (SNP&SEQ Technology Platform)": "Service", "National Genomics Infrastructure": "Service", "Bioinformatics Support for Computational Resources": "Service"}, "xrefs": [{"db": "pmc", "key": "PMC12501261"}, {"db": "pii", "key": "10.1038/s41418-025-01488-6"}], "notes": [], "created": "2025-09-08T06:54:49.956Z", "modified": "2025-11-28T10:45:02.518Z"}, {"entity": "publication", "iuid": "13e8aeb7d3f94c85981ecd78c1ad217a", "links": {"self": {"href": "https://publications.scilifelab.se/publication/13e8aeb7d3f94c85981ecd78c1ad217a.json"}, "display": {"href": "https://publications.scilifelab.se/publication/13e8aeb7d3f94c85981ecd78c1ad217a"}}, "title": "Loss of SNAI1 induces cellular plasticity in invasive triple-negative breast cancer cells.", "authors": [{"family": "Tsirigoti", "given": "Chrysoula", "initials": "C"}, {"family": "Ali", "given": "Mohamad Moustafa", "initials": "MM", "orcid": "0000-0002-4902-0550", "researcher": {"href": "https://publications.scilifelab.se/researcher/780c944670ff4d7489410895569ac257.json"}}, {"family": "Maturi", "given": "Varun", "initials": "V", "orcid": "0000-0003-1177-0839", "researcher": {"href": "https://publications.scilifelab.se/researcher/0bd84539b66b4e79964ec0330f1aefd7.json"}}, {"family": "Heldin", "given": "Carl-Henrik", "initials": "CH", "orcid": "0000-0002-9508-896X", "researcher": {"href": "https://publications.scilifelab.se/researcher/f705f7c509904a1db721ace2267ca48f.json"}}, {"family": "Moustakas", "given": "Aristidis", "initials": "A", "orcid": "0000-0001-9131-3827", "researcher": {"href": "https://publications.scilifelab.se/researcher/6c1626d991f3485e81232db174537e6d.json"}}], "type": "journal article", "published": "2022-09-28", "journal": {"title": "Cell Death Dis", "issn": "2041-4889", "volume": "13", "issue": "9", "pages": "832", "issn-l": "2041-4889"}, "abstract": "The transcription factor SNAI1 mediates epithelial-mesenchymal transition, fibroblast activation and controls inter-tissue migration. High SNAI1 expression characterizes metastatic triple-negative breast carcinomas, and its knockout by CRISPR/Cas9 uncovered an epithelio-mesenchymal phenotype accompanied by reduced signaling by the cytokine TGF\u03b2. The SNAI1 knockout cells exhibited plasticity in differentiation, drifting towards the luminal phenotype, gained stemness potential and could differentiate into acinar mammospheres in 3D culture. Loss of SNAI1 de-repressed the transcription factor FOXA1, a pioneering factor of mammary luminal progenitors. FOXA1 induced a specific gene program, including the androgen receptor (AR). Inhibiting AR via a specific antagonist regenerated the basal phenotype and blocked acinar differentiation. Thus, loss of SNAI1 in the context of triple-negative breast carcinoma cells promotes an intermediary luminal progenitor phenotype that gains differentiation plasticity based on the dual transcriptional action of FOXA1 and AR. This function of SNAI1 provides means to separate cell invasiveness from progenitor cell de-differentiation as independent cellular programs.", "doi": "10.1038/s41419-022-05280-z", "pmid": "36171192", "labels": {"NGI Short read": "Service", "NGI Uppsala (SNP&SEQ Technology Platform)": "Service", "National Genomics Infrastructure": "Service", "Bioinformatics Support for Computational Resources": "Service"}, "xrefs": [{"db": "pmc", "key": "PMC9519755"}, {"db": "pii", "key": "10.1038/s41419-022-05280-z"}], "notes": [], "created": "2022-11-29T09:54:47.071Z", "modified": "2024-01-16T13:48:34.962Z"}, {"entity": "publication", "iuid": "34ae3216e2364627b19b470684323d89", "links": {"self": {"href": "https://publications.scilifelab.se/publication/34ae3216e2364627b19b470684323d89.json"}, "display": {"href": "https://publications.scilifelab.se/publication/34ae3216e2364627b19b470684323d89"}}, "title": "TGF\u03b2 selects for pro-stemness over pro-invasive phenotypes during cancer cell epithelial-mesenchymal transition.", "authors": [{"family": "Tsubakihara", "given": "Yutaro", "initials": "Y"}, {"family": "Ohata", "given": "Yae", "initials": "Y", "orcid": "0000-0002-5518-835X", "researcher": {"href": "https://publications.scilifelab.se/researcher/ca5c2da2b3d84f5ea796361868ddbe5f.json"}}, {"family": "Okita", "given": "Yukari", "initials": "Y", "orcid": "0000-0002-7279-4634", "researcher": {"href": "https://publications.scilifelab.se/researcher/82ffe4fba4894ee1aebb444b41046c35.json"}}, {"family": "Younis", "given": "Shady", "initials": "S", "orcid": "0000-0002-4319-1738", "researcher": {"href": "https://publications.scilifelab.se/researcher/39b77c6e3ed14b9ba2e10132f89ef781.json"}}, {"family": "Eriksson", "given": "Jens", "initials": "J", "orcid": "0000-0002-8945-2665", "researcher": {"href": "https://publications.scilifelab.se/researcher/b94e7f542841474d86d53aa48958f870.json"}}, {"family": "Sellin", "given": "Mikael E", "initials": "ME", "orcid": "0000-0002-8355-0803", "researcher": {"href": "https://publications.scilifelab.se/researcher/f797357bcd3d4447bff96c20873dd500.json"}}, {"family": "Ren", "given": "Jiang", "initials": "J"}, {"family": "Ten Dijke", "given": "Peter", "initials": "P", "orcid": "0000-0002-7234-342X", "researcher": {"href": "https://publications.scilifelab.se/researcher/299812073080446a91fc6228efbdc1c5.json"}}, {"family": "Miyazono", "given": "Kohei", "initials": "K", "orcid": "0000-0001-7341-0172", "researcher": {"href": "https://publications.scilifelab.se/researcher/7a14a58f628d435a94ad9540478117cb.json"}}, {"family": "Hikita", "given": "Atsuhiko", "initials": "A", "orcid": "0000-0001-9552-2976", "researcher": {"href": "https://publications.scilifelab.se/researcher/b6a91722cadc4a7facd16457ed23d901.json"}}, {"family": "Imamura", "given": "Takeshi", "initials": "T", "orcid": "0000-0001-5101-4304", "researcher": {"href": "https://publications.scilifelab.se/researcher/ae63b202e284486eb903f18f78a8a024.json"}}, {"family": "Kato", "given": "Mitsuyasu", "initials": "M", "orcid": "0000-0001-9905-2473", "researcher": {"href": "https://publications.scilifelab.se/researcher/a2badf9539854c4381da91f37aa0c867.json"}}, {"family": "Heldin", "given": "Carl-Henrik", "initials": "CH", "orcid": "0000-0002-9508-896X", "researcher": {"href": "https://publications.scilifelab.se/researcher/f705f7c509904a1db721ace2267ca48f.json"}}, {"family": "Moustakas", "given": "Aristidis", "initials": "A", "orcid": "0000-0001-9131-3827", "researcher": {"href": "https://publications.scilifelab.se/researcher/6c1626d991f3485e81232db174537e6d.json"}}], "type": "journal article", "published": "2022-06-00", "journal": {"title": "Mol Oncol", "issn": "1878-0261", "volume": "16", "issue": "12", "pages": "2330-2354", "issn-l": "1574-7891"}, "abstract": "Transforming growth factor \u03b2 (TGF\u03b2) induces epithelial-mesenchymal transition (EMT), which correlates with stemness and invasiveness. Mesenchymal-epithelial transition (MET) is induced by TGF\u03b2 withdrawal and correlates with metastatic colonization. Whether TGF\u03b2 promotes stemness and invasiveness simultaneously via EMT remains unclear. We established a breast cancer cell model expressing red fluorescent protein (RFP) under the E-cadherin promoter. In 2D cultures, TGF\u03b2 induced EMT, generating RFPlow cells with a mesenchymal transcriptome, and regained RFP, with an epithelial transcriptome, after MET induced by TGF\u03b2 withdrawal. RFPlow cells generated robust mammospheres, with epithelio-mesenchymal cell surface features. Mammospheres that were forced to adhere generated migratory cells, devoid of RFP, a phenotype which was inhibited by a TGF\u03b2 receptor kinase inhibitor. Further stimulation of RFPlow mammospheres with TGF\u03b2 suppressed the generation of motile cells, but enhanced mammosphere growth. Accordingly, mammary fat-pad-transplanted mammospheres, in the absence of exogenous TGF\u03b2 treatment, established lung metastases with evident MET (RFPhigh cells). In contrast, TGF\u03b2-treated mammospheres revealed high tumour-initiating capacity, but limited metastatic potential. Thus, the biological context of partial EMT and MET allows TGF\u03b2 to differentiate between pro-stemness and pro-invasive phenotypes.", "doi": "10.1002/1878-0261.13215", "pmid": "35348275", "labels": {"Bioinformatics Support for Computational Resources": "Service"}, "xrefs": [{"db": "pmc", "key": "PMC9208077"}, {"db": "RefSeq", "key": "E-MTAB-97509"}], "notes": [], "created": "2022-11-09T15:57:22.355Z", "modified": "2024-01-16T13:48:36.266Z"}, {"entity": "publication", "iuid": "a5d51dc3032f481e9020d1483b809ab8", "links": {"self": {"href": "https://publications.scilifelab.se/publication/a5d51dc3032f481e9020d1483b809ab8.json"}, "display": {"href": "https://publications.scilifelab.se/publication/a5d51dc3032f481e9020d1483b809ab8"}}, "title": "BMP signaling is a therapeutic target in ovarian cancer.", "authors": [{"family": "Fukuda", "given": "Tomohiko", "initials": "T"}, {"family": "Fukuda", "given": "Risa", "initials": "R"}, {"family": "Tanabe", "given": "Ryo", "initials": "R"}, {"family": "Koinuma", "given": "Daizo", "initials": "D"}, {"family": "Koyama", "given": "Hiroo", "initials": "H"}, {"family": "Hashizume", "given": "Yoshinobu", "initials": "Y"}, {"family": "Moustakas", "given": "Aristidis", "initials": "A", "orcid": "0000-0001-9131-3827", "researcher": {"href": "https://publications.scilifelab.se/researcher/6c1626d991f3485e81232db174537e6d.json"}}, {"family": "Miyazono", "given": "Kohei", "initials": "K"}, {"family": "Heldin", "given": "Carl-Henrik", "initials": "CH", "orcid": "0000-0002-9508-896X", "researcher": {"href": "https://publications.scilifelab.se/researcher/f705f7c509904a1db721ace2267ca48f.json"}}], "type": "journal article", "published": "2020-12-05", "journal": {"title": "Cell Death Discov", "issn": "2058-7716", "issn-l": "2058-7716", "volume": "6", "issue": "1", "pages": "139"}, "abstract": "BMP signaling has been found to have tumor-promoting as well as tumor-suppressing effects in different types of tumors. In this study, we investigated the effects of BMP signaling and of BMP inhibitors on ovarian cancer (OC) cells in vitro and in vivo. High expression of BMP receptor 2 (BMPR2) correlated with poor overall survival of OC patients in the TCGA dataset. Both BMP2 and BMPR2 enhanced OC cell proliferation, whereas BMP receptor kinase inhibitors inhibited OC cell growth in cell culture as well as in a mouse model. BMP2 also augmented sphere formation, migration, and invasion of OC cells, and induced EMT. High BMP2 expression was observed after chemotherapy of OC patients in the GSE109934 dataset. In accordance, carboplatin, used for the treatment of OC patients, increased BMP2 secretion from OC cells, and induced EMT partially via activation of BMP signaling. Our data suggest that BMP signaling has tumor-promoting effects in OC, and that BMP inhibitors might be useful therapeutic agents for OC patients. Considering that carboplatin treatment augmented BMP2 secretion, the possibility to use a combination of BMP inhibitors and carboplatin in the treatment of OC patients, would be worth exploring.", "doi": "10.1038/s41420-020-00377-w", "pmid": "33298901", "labels": {"National Genomics Infrastructure": "Service", "NGI Uppsala (SNP&SEQ Technology Platform)": "Service"}, "xrefs": [{"db": "pii", "key": "10.1038/s41420-020-00377-w"}, {"db": "pmc", "key": "PMC7719168"}], "notes": [], "created": "2021-01-11T06:31:10.635Z", "modified": "2021-11-10T12:44:15.555Z"}, {"entity": "publication", "iuid": "680565f978934fedb42fa5ba80bbc4fe", "links": {"self": {"href": "https://publications.scilifelab.se/publication/680565f978934fedb42fa5ba80bbc4fe.json"}, "display": {"href": "https://publications.scilifelab.se/publication/680565f978934fedb42fa5ba80bbc4fe"}}, "title": "The ALK-1/SMAD/ATOH8 axis attenuates hypoxic responses and protects against the development of pulmonary arterial hypertension.", "authors": [{"family": "Morikawa", "given": "Masato", "initials": "M", "orcid": "0000-0002-6191-7176", "researcher": {"href": "https://publications.scilifelab.se/researcher/7ff787ffdf444850b9e4906c8c95fa92.json"}}, {"family": "Mitani", "given": "Yoshihide", "initials": "Y"}, {"family": "Holmborn", "given": "Katarina", "initials": "K"}, {"family": "Kato", "given": "Taichi", "initials": "T", "orcid": "0000-0001-7084-4565", "researcher": {"href": "https://publications.scilifelab.se/researcher/a737a920309943d48f55ccbedd02fd6c.json"}}, {"family": "Koinuma", "given": "Daizo", "initials": "D", "orcid": "0000-0001-5611-2122", "researcher": {"href": "https://publications.scilifelab.se/researcher/cf10583b944248b19c07772a0b364684.json"}}, {"family": "Maruyama", "given": "Junko", "initials": "J"}, {"family": "Vasilaki", "given": "Eleftheria", "initials": "E", "orcid": "0000-0001-6743-8523", "researcher": {"href": "https://publications.scilifelab.se/researcher/9b2aa70aa68a48f7870b664caf9ca3b3.json"}}, {"family": "Sawada", "given": "Hirofumi", "initials": "H", "orcid": "0000-0001-8069-5751", "researcher": {"href": "https://publications.scilifelab.se/researcher/cf45576856c9452888d08842b88669ca.json"}}, {"family": "Kobayashi", "given": "Mai", "initials": "M"}, {"family": "Ozawa", "given": "Takayuki", "initials": "T"}, {"family": "Morishita", "given": "Yasuyuki", "initials": "Y"}, {"family": "Bessho", "given": "Yasumasa", "initials": "Y"}, {"family": "Maeda", "given": "Shingo", "initials": "S", "orcid": "0000-0002-2737-3902", "researcher": {"href": "https://publications.scilifelab.se/researcher/152d321d11944b3ca9eb3ef387e70cd0.json"}}, {"family": "Ledin", "given": "Johan", "initials": "J", "orcid": "0000-0002-7319-7735", "researcher": {"href": "https://publications.scilifelab.se/researcher/92e482abc18c49d881d3bf0132b3fbcd.json"}}, {"family": "Aburatani", "given": "Hiroyuki", "initials": "H", "orcid": "0000-0003-0438-1544", "researcher": {"href": "https://publications.scilifelab.se/researcher/5bce060d4ff8446dbafc86bf5e3a001d.json"}}, {"family": "Kageyama", "given": "Ryoichiro", "initials": "R"}, {"family": "Maruyama", "given": "Kazuo", "initials": "K", "orcid": "0000-0003-3685-6348", "researcher": {"href": "https://publications.scilifelab.se/researcher/dd2eaad9217344a89fcc666951831e75.json"}}, {"family": "Heldin", "given": "Carl-Henrik", "initials": "CH", "orcid": "0000-0002-9508-896X", "researcher": {"href": "https://publications.scilifelab.se/researcher/f705f7c509904a1db721ace2267ca48f.json"}}, {"family": "Miyazono", "given": "Kohei", "initials": "K", "orcid": "0000-0001-7341-0172", "researcher": {"href": "https://publications.scilifelab.se/researcher/7a14a58f628d435a94ad9540478117cb.json"}}], "type": "journal article", "published": "2019-11-12", "journal": {"title": "Sci Signal", "issn": "1937-9145", "volume": "12", "issue": "607", "pages": "eaay4430", "issn-l": "1945-0877"}, "abstract": "Dysregulated bone morphogenetic protein (BMP) signaling in endothelial cells (ECs) is implicated in vascular diseases such as pulmonary arterial hypertension (PAH). Here, we showed that the transcription factor ATOH8 was a direct target of SMAD1/5 and was induced in a manner dependent on BMP but independent of Notch, another critical signaling pathway in ECs. In zebrafish and mice, inactivation of Atoh8 did not cause an arteriovenous malformation-like phenotype, which may arise because of dysregulated Notch signaling. In contrast, Atoh8-deficient mice exhibited a phenotype mimicking PAH, which included increased pulmonary arterial pressure and right ventricular hypertrophy. Moreover, ATOH8 expression was decreased in PAH patient lungs. We showed that in cells, ATOH8 interacted with hypoxia-inducible factor 2\u03b1 (HIF-2\u03b1) and decreased its abundance, leading to reduced induction of HIF-2\u03b1 target genes in response to hypoxia. Together, these findings suggest that the BMP receptor type II/ALK-1/SMAD/ATOH8 axis may attenuate hypoxic responses in ECs in the pulmonary circulation and may help prevent the development of PAH.", "doi": "10.1126/scisignal.aay4430", "pmid": "31719172", "labels": {"Genome Engineering Zebrafish": "Collaborative"}, "xrefs": [{"db": "pii", "key": "12/607/eaay4430"}, {"db": "pmc", "key": "PMC6908447"}, {"db": "mid", "key": "EMS85032"}], "notes": [], "created": "2019-12-02T16:11:40.604Z", "modified": "2021-06-16T16:18:32.543Z"}]}